The present invention relates generally to ultrasonic measurements of biological tissue parameters for medical diagnostics, and more particularly to a method and a device for measurements of ultrasound velocity in tissue aimed at determination of hydration in infants.
Dehydration remains a leading cause of infant morbidity and mortality worldwide. In the United States, dehydration accounts for at least 10% of hospital admissions. Today, physical examination remains the most used bedside tool to detect dehydration and yet, its sensitivity remains suboptimal. Laboratory tests such as BUN (blood urea nitrogen) and bicarbonate levels require blood draws, and have been reported to be non-diagnostic unless they are extremely abnormal. The combination of history, exam and laboratory tests appears to have the best diagnostic value when assessing the hydration status of a child. However, examiners vary significantly in their agreement. Therefore, the non-invasive, objective bedside assessment of a sick infant's hydration status remains a challenge.
Physical signs of moderate to severe dehydration in children represent a significant 6 to 10% water loss. In infants less than 10 kg, the same signs represent an even more dangerous water loss of 10 to 15%. Hence, young children under 5 years old have higher risk for morbidity due to dehydration and require earlier medical response.
The clinical state of dehydration disrupts life sustaining processes at the organic and cellular level. Its clinical manifestations indicate total body water depletion leading to poor intravascular volume. The body system protectively shunts blood towards the most vital organs (heart, kidney and brain) and away from peripheral organs such as the intestines, muscles and skin. Hence, the earliest sign of dehydration may be seen in the skin and muscle tissues. If allowed to persist, the eventual result is tissue hypo-perfusion and inadequate oxygen delivery to end organs. A reduced extracellular fluid volume leads to cellular dehydration, oxygen debt and lactic acid production, which promotes further deterioration. In addition, electrolyte imbalances disrupt cellular energy metabolism and transport. The terminal phase is hypovolemic shock, multi-organ failure and death.
Sick infants have a delicate fluid and electrolyte balance that can rapidly deteriorate or be worsened iatrogenically if the water balance is not monitored closely. A non-invasive device and method of quantifying hydration in infants would be useful in the following clinical scenarios:                (a) In situations of excessive fluid loss or poor fluid intake, knowing organ tissue water contents can guide fluid resuscitation efforts. Currently, tools for assessing fluid balance are the physical examination, urine output and strict intake/output logs. Unfortunately, even the most indicative findings of poor hydration such as increased capillary refill time, abnormal skin turgor, and abnormal respiratory pattern have only modest sensitivity. Despite better performance when using classification tables that combine the diagnostic value of two or more signs, there remains the significant problem of inconsistent inter-examiner agreement. Infant hydration monitor offers an opportunity to obtain reproducible quantitative measures of tissue water content that potentially can complement traditional qualitative methods of assessing a patient's hydration status;        (b) Neonates, especially premature ones, have a very high insensible water loss to the environment (80-100 cc/kg/d) due to a poorly keratinized skin layer and a large surface area to volume ratio. Too much fluid can be loss easily leading to dehydration. Less than expected loss can mean extra fluid that contributes to lung edema in premature infants with respiratory distress syndrome. Currently in the neonatal intensive care unit (NICU), day-to-day estimates of total body water content and fluid management for each patient relies mainly on analyzing weight trends. Total body water content in neonates comprises 75-90% (premature infants having the highest portion) of the body weight, suggesting that weight changes may still be a fairly good indicator of water content shifts over time. Losing or gaining 100 gm generally correlates with a 10% shift for 1 kg premature infant. Using weight can be problematic in neonates who are too unstable to be moved onto a scale. Built-in bed scales tend to overestimate weights. Furthermore, organ growth is expected to contribute approximately 10-15 gm/kg daily depending on the balance between nutritional intake and energy expenses. It is natural to expect that changes in local tissue hydration reflect total body water content (TBWC) in neonates;        (c) For sick neonates, monitoring local tissue hydration may have value in quantifying capillary leak syndrome—a physiologic state in which increased capillary permeability lead to general edema, low intravascular volume, and organic mal-perfusion. Neonatal capillaries are more vulnerable to physiologic insults. Some authors suggested that higher levels of vascular endothelial growth factor in neonates may lead to a higher incident of capillary leak syndrome after cardiopulmonary bypass. Sick neonates developing capillary leak syndrome often have a spike gain in weight. As fluid and solutes ‘leak’ into the interstitial space, a vicious cycle ensues that require more fluid administration in order to maintain adequate intravascular volume and organ perfusion. Hence especially in sick neonates, monitoring local tissue hydration with a hydration monitor in conjunction with other physiological data such as blood pressure and laboratory studies may help track and quantify the interstitial movement of fluid in critically ill patients with capillary leak syndrome;        (d) Cardiac failure and venous thrombosis are clinical conditions that increase intravascular hydrostatic pressure and cause peripheral edema. Quantifying the edema can help determine the severity of disease. Currently, the physical examination offers the best non-invasive, ‘simple to use’ qualitative method—using a four grade scale measuring the depth of indentation made by finger pressure over a bony prominence. Unfortunately, the exam has suboptimal sensitivity and becomes apparent late in the clinical pathophysiological course. Other methods using computer tomography, magnetic resonance, and musculoskeletal ultrasonography to characterize edema rely on expert radiologists with special training and equipment not available at the bedside. Infant hydration monitor is a portable device and its ability to detect small changes in tissue water content (as little as 2%) may discover peripheral edema earlier than physical exam, perhaps triggering earlier intervention. Infant hydration monitor may clarify information gained thru current methods of estimating intravascular blood volume (i.e. echocardiogram or central venous pressure catheter, CVP). For instance, poor intravascular volume may ‘yield’ a normal CVP if there is right sided heart failure. The latter condition would increase venous hydrostatic pressure and lead to increase peripheral edema at the lower legs, detectable by infant hydration monitor;        (e) Unilateral limb edema is an important physical sign of venous thrombosis (VT) that requires rapid response and treatment. Its serious complications include renal insufficiency, pulmonary embolism, and stroke. In the neonatal population, indwelling catheters in the inferior vena cava can cause venous thromboses and it is standard practice to exam the associated limb daily for edema. Infant hydration monitor offers a quantitative measure of edema that may be more sensitive than the physical exam, enabling earlier detection of VT.        
There are several methods for assessing total body water, as the most prominent indicator of hydration status. Most of these methods are based on bioelectrical impedance and conductance methods. U.S. Pat. No. 4,008,712 issued to Nyboer discloses method and apparatus for performing electrical measurement of body electrical impedances to determine changes in total body water in normal and deranged states of the body, U.S. Pat. No. 5,615,689 issued to Kotler discloses a method of predicting body cell mass using impedance analysis, U.S. Pat. No. 6,280,396 issued to Clark discloses an apparatus and method for measuring subject's total body water content by measuring the impedance of the body, and U.S. Pat. No. 6,459,930 issued to Takehara et al. discloses a dehydration condition judging apparatus by measuring bioelectric impedance.
The aqueous tissues of the body, due to their dissolved electrolytes, are the major conductors of an electrical current, whereas body fat and bone have relatively poor conductance properties. Significant technical problems eliminated the viability of many electrical methods for in vivo body composition analyses. Oversimplifications in formulae in the standard biological impedance analysis methods lead to problems.
There is also known a more complex approach, based on measuring resistance and reactance over a wide range of frequencies. The technique based on this approach is called bioelectrical impedance spectroscopy. U.S. Pat. No. 6,125,297 issued to Siconolfi discloses a method and apparatus for determining volumes of body fluids in a subject using bioelectrical response spectroscopy.
Regardless of the choice of single or multifrequency method, the impedance index alone is not an accurate predictor. Additional anthropometric terms (i.e., weight, age, gender, race, shoulder width, girth, waist-to-hip ratio, body mass index) need to be included in the prediction model to reduce the standard error of the estimate. In summary, the downside of the water content assessment methods based on the measurements of electrical properties of tissues is low accuracy, significant dependence of testing results on the anthropometrical features of the subject and on electrolyte balance.
None of the known prior art devices are easily adaptable for use with neonates and infants. To assess the hydration status of an infant, most practitioners rely simply on the bedside physical examination. The patient's daily weights and fluid in/fluid out are recorded. Limitations of this approach include: (1) the mentioned measures do no reflect the real hydration status in tissues directly; (2) critical patients can not be moved onto a scale and (3) bed scales have difficulty calibrating due to the equipment on the bed and using them still requires the baby to be lifted off the bed for zeroing procedures.
Since trans-epidermal water loss is a major cause of water loss in premature infants during the first week after birth, devices called evaporimeters have been developed to measure the evaporative water loss in infants. The evaporimeters reflect permeability of the stratum corneum and the infant's immature skin barrier function, but do not allow judgment regarding water deficit in the tissues or the whole organism.
Advanced laboratory techniques for assessment of body composition are potentially applicable in infants, including D2O dilution, bioelectrical impedance spectroscopy (BLA/BIS), total body electrical conductivity (TOBEC), total body potassium (TBK), and dual x-ray absorption (DXA) that can estimate total body water, total body potassium, fat-free body mass and fat content. Physicians in the neonatal intensive care unit have used BIS to guide fluid administration in newborns during the postpartum period. However for premature infants, these techniques are impractical for frequent monitoring of hydration status because they: need blood or urine samples, involve labor consuming analysis, use large equipment, have low precision (BIS), require patient transportation, and are not specific to tissue hydration.
There is therefore a need for a simple and highly accurate method and device for monitoring infant tissue hydration status.